Reduction of nitroolefins to amines



United States Patent Delaware Filed Dec. 29, 1960, Ser. No. 79,158

No Drawing.

8 Claims. (Cl. ass-570.8

This application relates to a novel chemical synthesis, and moreparticularly to an improved process for the reduction of nitroolefins tothe corresponding amines.

In United States Patents Nos. 2,636,901 and 2,647,930, there aredisclosed processes for reducing nitroolefins to form a mixture of thecorresponding ketones and the corresponding amines. By a careful controlof the operating conditions, the practitioner is able to produce eithera predominant amount of amine or a predominant amount of ketone,depending upon the particular product sought. In all instances, however,the reaction product is a mixture of both the ketone and the amine. Thisof course necessitates a separation of the reaction mixture in order toobtain the desired compound in substantially pure form. Moreover, whereonly one compound is sought, such as the amine, the formation of theketone as well as the amine substantially reduces the overall yield.While this is not necessarily significant on the laboratory scale, itshould be apparent that on the commercial scale, an increase in yield isextremely desirable, if not critical.

The present invention relates in essence to an improvement over theprocesses disclosed in the aforementioned .patents wherein nitroolefinsare reduced to form the corresponding amine, the reaction mixture beingsubstantially free from undesired ketone.

It is therefore one object or this invention to provide a process forproducing amines in increased yields.

Another object is to produce amines in increased yields not heretoforeobtainable by subjecting nitroolefins to the action of molecularhydrogen in the presence of a hydrogenation catalyst and an organicacid.

Other objects of the invention will in part be obvious and will in partappear hereinafter.

The aforementioned United States Patent No. 2,636,901 discloses aprocess for preparing a mixture of amines and ketones by subjectingnitroolefins to the action of molecular hydrogen in the presence of aRaney nickel catalyst and an organic acid. The presence of an organicacid is necessary in order to eliminate or minimize the formation ofundesirable condensation products which otherwise may be produced inlarge amounts. By varying the amount of water present and the strengthof the organic acid employed, either a preponderance of amine or apreponderance of ketone is obtained. As taught in the patent, where apreponderance of amine is sought, weak organic acids such as acetic acidshould be employed if a small amount of water is present in the reactionmedium. If, on the other hand, the reaction medium is substantiallyanhydrous, stronger organic acids may be employed. The patent teachesthat the reaction is complete when substantially all of the nitroolefinis reduced to a mixture of amine and ketone. Thus, when following theteachings of the patent, the reaction is considered as completed when ithas slowed down to a point where, relatively speaking, very littlehydrogen is taken up.

It has now been found, quite surprisingly, that if the reduction isallowed to continue further, substantially all of the ketone previouslyformed is converted to the corresponding amine. In other words, it hasbeen discovered by the applicant that an appreciably increased yield ofamines may be obtained by reducing nitroolefins in what may be regardedas a two-step reduction: (1) a first step 'following the teachings ofthe aforementioned patents wherein a nitroolefin is reduced to form amixture of amine and ketone; and (2) a second step in which the mixtureof ketone and amine is further subjected to molecular hydrogen untilsubstantially all of the unwanted ketone is converted to the desiredamine.

The present invention therefore comprises the step of reducing anitroolefin with molecular hydrogen in the presence of a hydrogenationcatalyst, and more particularly, a Raney nickel catalyst and an organicacid, e.g., an aliphatic carboxylic acid, until the reaction mixturecontains substantially no ketone and contains essentially only thedesired amine.

Nitroolefins which may be satisfactorily reduced by the presentinvention may be represented by the following general structuralformula:

wherein R may be alkyl, preferably lower alkyl, or aryl and R is loweralkyl, such as methyl, ethyl, isopropyl, etc. It will be understood thatthe corresponding nitroolefins in which the alkyl or aryl radical issubstituted also may be employed in the present invention, sinceobviously various substituents may be present in such alkyl and arylradicals without afiecting the reaction mechanism.

In the preferred embodiments, R is phenyl, or a substituted phenylradical, such as tolyl; a dialkoxyphenyl, such as 1,4-dimethoxyphenyl;or halo, lower alkyl or lower alkoxy derivatives of such radicals. Asexamples of nitroolefins within the above formula which can be reducedaccording to the present invention, mention may be made ofl-phenyl-2-nitro-1-butene, 1-(p-isopropylphenyl)-2-nitro-propene,l-(m-tolyl)-2-nitro-propene, 2 nitro-2 hexene,l-phenyl-2-nitro-l-propene, 4-phenyl-2-nitro-2 pentene,1-(p-methoxyphenyl)-2-nitro-propene and 1-(2,5-dimethoxyphenyl)-2-nitro-l-propene.

As was indicated previously, it the reduction is permitted to continuefor a period of time longer than that which is necessary to reduce thenitroolefin to a mixture of ket-one and amine, the reaction product willbe substantially free of undesired ketone, the ketone having beenconverted to the corresponding amine. This fact that the desired aminecan be obtained from the ketone which is unwanted and is in effectregarded as an impurity is quite unexpected and is the essence of thepresent invention.

The initial stage of the reaction, wherein the nitroolefin is convertedto a mixture of ketone and amine, is a highly exothermic reaction whichmay be carried out at pressures and temperature such as taught in theaforementioned patents. In other words, the initial stage may be carriedout at temperatures of about 40 to about 100 C., and at pressures of theorder of 5:00 to 2,000 pounds per square inch. Particularly good resultshave been obtained at pressures of about 800 to 1,200 pounds per squareinch and temperatures from about 55 to C.

It should be noted that, in the initial stage, the greater thetemperature beyond 80 C., the greater is the tendency for polymerizationor production of undesired by-prodnets, and hence, the lower the overallyield.

The time of reaction in the initial stage will vary in accordance withthe operating conditions and may, for example, be in the order of anhour or more. In any event, the initial stage is completed when theexotherm has substantially subsided and the temperature stabilizes.

The second stage, wherein the mixture of ketone and amine formed in theinitial stage is further treated until substantially all of the ketoneis converted into amine, requires appreciably less hydrogen forcompletion, say, for example, 5% of the total hydrogen, and may becarried out at the same temperature as the initial stage or atconsiderably higher temperatures. It should be noted that the roughlyadditionalhydrogen taken up in the second stage produces at least a 20%increase in yield of amine. If the second stage is carried out at thesame temperature, the reaction time for converting substantially all ofthe ketone to amine is considerably longer than'the reaction'time ofthefirst stage. In this respect, it should be noted that the reactiontime for completion of the secperatures, say at 120 C., or higher,without being confronted with the danger of reducing the yield due topolymerization and formation of other by-products, as was true in theinitial stage. Thus, in the preferred embodiment, the temperature israised following completion of the initial stage, thereby reducing theoverall reaction time.

In order to understand more clearly the nature and scope of thepresentinvention, the reactions occurring in' each of the two stagesare-described below in more particularity.

In the initial stage of the reduction, the riitroolefinis reduced toform a mixture of amine and ketone, according to the following generalreaction:

R-CH-Cfi-NO, R-CH -CH-NH; R-CH,C=0

R1 IIU R1 While the amine is 'prepared directly by the reduction acidssuch as chloropropionic acid, bromopropionic acid, and the like, due tothe harmful effect of the halogen on the catalyst.

While the use of a Raney nickel catalyst has been described for purposesof illustrating the invention, it is within the scope of the inventionto employ other suitable catalysts of equivalent function. Thus, theinvention should not be construed as limited to the use of a Raneynickel catalyst. As examples of other catalysts which may be employed,mention may be made of'palladium on barium sulfate and Girdler G49Anickel catalyst (a stabilized catalyst with atmolecular film of oxygen).

Where found desirable or expedient to do so, suitable organic solventsmay be used in the reaction medium along of the nitroolefin,-it isbelieved that theketone is prepared by the following sequence of steps:

acid to form the ammonium salt thereof.

It is at this point that the prior art stops the reaction. However,ithas now been discovered that, due to the presence'of ammonia in thereaction mixture, if the reaction is permitted to continue, the ketoneis slowly reduced to the corresponding amine, according to the followinggeneral reaction:

In carrying out the process of this invention, the strength ordissociation constant of the organic acid employed, is not particularlycritical, as was the case in the processes described in theaforementioned patents. Likewise, the presence of water is not acriticalfactor to the end result. This is true since it is not critical whetherthe initial stage produces 'a'preponderance of amine or a preponderanceof ketone. a v

Since the strength or dissociation constant of the organic acid employedis not critical, as was the-case in the processes described in theaforementioned patents, any of the organic acids such as were recited inthe patents and having an ionization constant at 25 C., between about1.4 10 and 1.1 X 10- may be employed. Examples of such acids are acetic,propionic, butyric, valeric, lactic, tartaric and formic acids. 7

The quantity of acid employed is not particularly critical and can vary.For maxim-um yield, however, it has been found-that at least one mole ofacid should be used for each mole of nitroolefin.

The term organic acid as applied to this invention does not include thehalogen derivatives of the organic with the organic acid and the Raneynickel catalyst. Solvents which may be employed maybe selected from along list of organic solvents which are inert to the re- .actants andthe products formed by the reduction. As examples of useful organicsolvents, mention may be mad'e'of alcohols such as'm'e'thanol, ethanoland propanol; ethers such as ethyl ether, propyl ether and ethyl hexylether; esters such as methyl'acetate, ethyl for-mate and ,amyl acetate,and various acids and hydrocarbon solvents well known in the art.

The following example shows by way of illustration and not byway oflimitation the process of this invention, the invention not beinglimited to the ingredients, proportions, time of treatment, and otheropera ting conditions recited therein.

Example 1 A five gallon high-pressure autoclave was charged with thefollowing materials:

The autoclave was closed and flushediseveral times with nitrogen. It wasthen heated to 55 to 60 C., and hydrogen was introduced at a pressure-of1,200 pounds per square inch. A strong exotherm occurred and thetemperature was controlled by cooling to remain at 65 to C. 'In about 1hour, the exotherm subsided and the autoclave stabilized atapproximately 65 C. (thereby indicating completion of the initial stagedescribed previously in the specification). The temperature was thenincreased to 120 C., and maintained for 60 to '90 minutes. -A smallerhydrogen uptake was noted being about 5% of the total hydrogen taken up.The autoclave was then cooled, discharged, flushed with nitrogen and discharged with nitrogen pressure. was collected and purified, and 2,260grams of }8 -(2,5 dimethoxyphenyl)-u-methyl-ethylamine, representing a74% total yield, were recovered.

a The following example confirms the reaction whereby a. ketone isconverted to the corresponding amine.

The autoclave was closed, heated to C. and hydrogen was then introducedat a pressure of 1,200 pounds per square nich. There was no rise intemperature. No measurable hydrogen was taken up after tWo hours,although the reaction was permitted to continue overnight.

At the end of this time, no noticeable amount of ketone remained.Analysis showed a yield ofB-(2',5-dimethoxyphenyl)-ct-methyl-ethylamine, 3% distillation residuesand 2% acid insolubles.

The reaction product Since certain changes may be made in the aboveprocess Without departing from the scope of the invention hereininvolved, it is intended that all matter contained in the abovedescription shall be interpreted as illustrative and not in a limitingsense.

What is claimed is:

"1. The process of preparing amines from nitroolefins which comprisescatalytically reducing a nitroolefin of the formula:

wherein R is selected from the group consisting of phenyl, alkyl-phenyl,alkoxy-phenyl, halo-phenyl and alkyl radicals and R is a lower alkylradical, with molecular hydrogen in the presence of an aliphaticcarboxylic acid to form a reaction mixture comprising the ammonium saltof said acid and the corresponding ketone and the corresponding amine ofsaid nit-roolefin, said reducing step being exothermic; and continuingsaid reducing for a period of at least one hour after the exotherm hassub stantially subsided and until substantially all of said ketone isconverted into said amine.

2. The process of preparing amines from nitroolefins which comprisescataly-tically reducing a nitroolefin of the formula:

wherein R is selected from the group consisting of phenyl, alkyl-phenyl,alkoxy-phenyl, halo phenyl and alkyl rad-icals and R is a lower alkylradical, with molecular hydrogen in the presence of an aliphaticcarboxylic acid to form a reaction mixture comprising the ammonium saltof said acid and the corresponding ketone and the corresponding amine ofsaid nitroolefin, said reducing step being exothermic; and continuingsaid reducing at a temperature of about 80 C. to at least 120 C. for aperiod of from about 1 to 16 hours after the exotherm has substantiallysubsided and until substantially all of said ketone is converted intosaid amine, said time of continued reducing being greater at said lowernamed temperatures and shorter at said higher named temperatures.

3. The process of preparing amines from nitroolefins which comprisescatalytically reducing a nitroolefin of the formula:

wherein R is selected from the group consisting of phenyl, alkyl-phenyl,alkoxy-phenyl, halo-phenyl and alkyl rad-icals and R is a lower alkylradical, with molecular hydrogen in the presence of an aliphaticcarboxylic acid at a temperature within the range of about 40 C. toabout 100 (3., to form a reaction mixture comprising the ammonium saltof said acid and the corresponding ketone and the corresponding amine ofsaid nitroolefin, said reducing step being exothermic; continuing saidreducing until the exotherm has substantially subsided; and thereafterelevating the temperature and reacting said reaction mixture withmolecular hydrogen until substantially all of said ketone is convertedinto said amine.

4. The process of preparing amines from nitroolefins which comprisescatalyt-ically reducing a nitr-oolefin of the formula:

wherein R is selected from the group consisting of phenyl,alkyl-p-henyl, alkoxy-phenyl, halo-phenyl and alkyl radicals and R is alower alkyl radical, with molecular hy drogen in the presence of analiphatic carboxylic acid at a temperature wit-bin the range of about 40C. to about C., to form a reaction mixture comprising the ammonium saltof said acid and the corresponding ketone and the corresponding amine ofsaid nitroolefin, said reducing step being exothermic; continuing saidreducing until the exotherm has substantially subsided; and thereafterelevating the temperature to at least C. and continuing said reducingwith molecular hydrogen for about 60 to 90 minutes until substantiallyall of said ketone is converted into said amine.

5. The process as defined in claim 4 wherein the aliphatic carboxylicacid has an ionization constant at 25 C. of between about 1.4Xl0" and1.l *l0* and the reduction is effected in the presence of a Raney nickelcatalyst.

6. The process which comprises reducing1-(2',5'-dimethoxyphenyl)-2nitro-propene with molecular hydrogen in thepresence of an aliphatic carboxylic acid and a Raney nickel catalyst toform a reaction mixture of ketone and amine comprising respectivelyp-dimethoxyphenyl acetone and,6-'(2,5'-dirnethoxyphenyl)-m-methyl-ethylamine and the ammonium salt ofsaid acid, said reducing step being exothermic; and continuing saidreducing for a period of at least one hour after the exotherm hassubstantially subsided until substantially all of said ketone isconverted into said amine.

'7. The process which comprises reducingl-(2,5-dimethoxyphenyl)-2-nitro-propene with molecular hydrogen in thepresence of an aliphatic carboxylic acid and a Raney nickel catalyst toform a mixture of ketone and amine comprising respectivelyp-dimethoxyphenyl acetone andB-('2,5'-dirnet-hoxyphenyl)-a-methyl-ethylamine and the ammonium salt ofsaid acid, said reducing step being highly exothermic; continuing saidreducing until the exotherm has substantially subsided; and thereafterelevating the temperature to about 120 C. and continuing said reducingfor about 60 to 90 minutes until substantially all of said ketone isconverted into said amine.

8. The process as defined in claim 7 wherein said aliphatic carboxylicacid is acetic acid.

References Cited in the file of this patent UNITED STATES PATENTS2,636,901 Tindall Apr. 28, 1953 2,647,930 Tindall Aug. 4, 1953 3,062,884Green Nov. 6, 1962 OTHER REFERENCES Migrdichian: Organic Synthesis, vol.1, page 472 (1957), QB 266 M55.

1. THE PROCESS OF PREPARING AMINES FROM NITROOLEFINS WHICH COMPRISESCATALYTICALLY REDUCING A NITROOLEFIN OF THE FORMULA: